Some hexahydronaphthalene derivatives, e.g., lovastatin, atorvastatin, cerivastatin and simvastatin, are potent inhibitors of HMG-CoA(3-hydroxy-3-methylglutaryl CoA) reductase, the enzyme which controls the biosynthesis of cholesterol, and therefore, used widely for the treatment of hyperlipidemia, hypercholesterolemia, and others. In particular, simvastatin of formula (1) is favored over other hexahydronaphthalene derivatives because of the absence of adverse side effects and its high absorbability in the stomach. Also, it has been reported that simvastatin prevents and reduces the risk of Alzheimer's disease(AD) by retarding the production of Ab42, β-amyloid protein related to the outbreak of AD.

The synthesis of simvastatin from lovastatin have been conducted based mainly on one of the two following methods.
U.S. Pat. No. 5,393,893, U.S. Pat. No. 4,582,915, U.S. Pat. No. 5,763,646, U.S. Pat. No. 5,763,653, EP Patent No. 299,656 and International Patent Publication No. WO 99/45003 disclose a method of preparing simvastatin of formula (I) by way of direct methylation of the 8′-methylbutyryloxy side chain of lovastatin of formula (II) using a methyl halide in the presence of a metal amide base. However, this method has the disadvantage that the C-methylation step has to be carried out at an extremely low temperatures(−75 to −30° C.) using a strong base under anhydrous condition which is difficult to handle in mass production.

Another method disclosed in U.S. Pat. No. 4,444,784 is represented by Scheme 1. First, lovastatin of formula (II) is hydrolyzed with an excessive amount of lithium hydroxide to remove the 2-methylbutyryl side chain and to simultaneously open its 6-membered lactone ring to produce the triol acid of formula (III). The triol acid compound of formula (III) is then heated to obtain the diol lactone of formula (IV). The hydroxy group on the lactone ring of the diol lactone is protected to obtain the tert-butyldimethylsilyl ether of formula (V) and then the hydroxy group at C-8 of the hexahydronaphthalene ring system is acylated with 2,2-dimethylbutaonic acid in the presence of dicyclohexyl carbodiimide, or 2,2-dimethyl chloride to produce the compound of formula (VI). The t-butyldimethylsilyl protecting group of the compound of formula (VI) is then removed in the final step using tetrabutylammonium fluoride to produce simvastatin of formula (I):

However, this method requires a high temperature and 56 hours of long reaction time in the hydrolysis and acylation steps, which leads to a number of undesired side products, causing low yield and purity of the final product.
In addition, Korean Publication No. 2000-15179 discloses a modification of the method of reaction scheme 1, wherein t-BuOK is used in the hydrolysis step, and acyloxy triphenylphosphonium salts, in the acylation step. However, this method requires the use of t-BuOK which is expensive and causes unwanted side reaction and gives low yield, and excessively large amounts of reagents such as 2,2-dimethyl butanoic acid, triphenyl phosphine and N-bromosuccinimide, the unreacted reagents being removed by complicated purification procedures. Thus, like the other methods, this method is also not suitable for mass production.